Hydrochloric Acid → HCID 178522244, compound

HRID 660133Notes

Reaction equation

HRID 660133 reaction equation
[H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:8]([F:10])[CH:9]=1.[CH:15]1C=C(OC(OC2N=CC=CC=2)=S)N=CC=1.[NH:31]([C:33](=[O:55])[C:34]([NH:36][C:37]1[CH:54]=[CH:53][C:40]([O:41][C@@H:42]2[CH2:47][CH2:46][C@H:45]([C:48]([O:50]CC)=[O:49])[CH2:44][CH2:43]2)=[CH:39][CH:38]=1)=[O:35])[NH2:32].CCN=C=NCCCN(C)C.[OH-].[Na+].Cl>CN(C=O)C.CO.C1COCC1.O>[F:10][C:8]1[CH:9]=[C:4]([NH:3][C:15]2[O:55][C:33]([C:34]([NH:36][C:37]3[CH:54]=[CH:53][C:40]([O:41][C@@H:42]4[CH2:47][CH2:46][C@H:45]([C:48]([OH:50])=[O:49])[CH2:44][CH2:43]4)=[CH:39][CH:38]=3)=[O:35])=[N:31][N:32]=2)[CH:5]=[C:6]([C:11]([F:14])([F:12])[F:13])[CH:7]=1

Participants

12

Reactant 7

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 24758Sodium hydrideHCID 719784O,O-Dipyridin-2-yl carbonothioateHCID 27359133-Amino-5-fluorobenzotrifluorideHCID 178472469HCID 178472469, compound2×

Product 1

HCID 178522244HCID 178522244, compoundYield 44.1%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
85 °C

Procedure

Sodium hydride (60% dispersion in mineral oil, 192 mg, 4.80 mmol) was added to a stirred solution of 3-amino-5-fluorobenzotrifluoride (430 mg, 2.40 mmol) in DMF (10 mL) at ambient temperature. After 5 mins di-2-pyridyl thionocarbonate (557 mg, 2.40 mmol) was added in one portion and stirring was continued for 10 mins. Ethyl cis-4-(4-{[hydrazino(oxo)acetyl]amino}phenoxy)cyclohexanecarboxylate (Intermediate 1, 698 mg, 2.00 mmol) was added in one portion to the reaction mixture and stirred at 65° C. for 30 mins. EDCI (460 mg, 2.40 mmol) was then added in one portion and the reaction mixture was heated to 85° C. for 3 h. The mixture was cooled to ambient temperature and water (15 mL) was added and the resulting suspension was filtered to leave a cream solid. The solid was taken up in a mixture of MeOH (8 mL) and THF (4 mL) and a 2N aqueous solution of NaOH (4 mL) was added in one portion and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was acidified by the addition of 2M HCl and the resulting precipitate was filtered, washed with water (10 mL) and dried under high vacuum to leave a solid. The solid was recrystallised from refluxing glacial acetic acid to provide the title compound as a white solid (448 mg, 44%).

Workup

  1. stirringstirred at 65° C. for 30 mins
  2. temperatureThe mixture was cooled to ambient temperature
  3. filtrationthe resulting suspension was filtered
  4. customto leave a cream solid
  5. stirringthe reaction mixture was stirred at ambient temperature for 16 h
  6. filtrationthe resulting precipitate was filtered
  7. washwashed with water (10 mL)
  8. customdried under high vacuum
  9. customto leave a solid
  10. customThe solid was recrystallised
  11. temperaturefrom refluxing glacial acetic acid

Sources & evidence

ORD record
ord-dc311c494aa1429083189bf23d9a43fe
Source dataset
uspto-grants-2011_12
Patent number
US08084478B2

Reaction notes

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